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Li, Zhiguo

Overview:

survival analysis, dynamic treatment regimes, clinical trials

Positions:

Associate Professor of Biostatistics & Bioinformatics

Biostatistics & Bioinformatics
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 2008

Ph.D. — University of Michigan at Ann Arbor

Grants:

Pathological B Cells: Novel Strategies to Prevent and Treat Chronic GVHD

Administered By
Medicine, Cellular Therapy
AwardedBy
National Institutes of Health
Role
Biostatistician
Start Date
August 15, 2015
End Date
June 30, 2020

The Notch2-BCR Axis: Targeting Drivers of B cell Fate in Chronic GVHD

Administered By
Medicine, Cellular Therapy
AwardedBy
Leukemia & Lymphoma Society
Role
Statistician
Start Date
October 01, 2015
End Date
September 30, 2018

Statistical/Computational Methods for Pharmacogenomics and Individualized Therapy

Administered By
Biostatistics & Bioinformatics
AwardedBy
University of North Carolina - Chapel Hill
Role
Co Investigator
Start Date
May 15, 2015
End Date
March 31, 2017

Methods for Discovery and Analysis of Dynamic Treatment Regimes

Administered By
Biostatistics & Bioinformatics
AwardedBy
University of North Carolina - Chapel Hill
Role
Principal Investigator
Start Date
May 15, 2015
End Date
March 31, 2017

Validation of a microRNA signature for the prediction, diagnosis and prognosis of acute graft-versus-host disease

Administered By
Immunology
AwardedBy
Blood and Marrow Transplant Clinical Trials Network
Role
Biostatistician
Start Date
January 20, 2015
End Date
December 31, 2015

Plasma microRNAs as non-invasive biomarker for acute graft-versus-host diseases

Administered By
Immunology
AwardedBy
The Biomarker Factory
Role
Investigator
Start Date
February 01, 2014
End Date
April 30, 2015

Mayo Alliance Foundation Funds

Administered By
Duke Cancer Institute
AwardedBy
Mayo Foundation
Role
Statistician
Start Date
January 01, 2012
End Date
February 28, 2014
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Publications:

Comparison of adaptive treatment strategies based on longitudinal outcomes in sequential multiple assignment randomized trials.

In sequential multiple assignment randomized trials, longitudinal outcomes may be the most important outcomes of interest because this type of trials is usually conducted in areas of chronic diseases or conditions. We propose to use a weighted generalized estimating equation (GEE) approach to analyzing data from such type of trials for comparing two adaptive treatment strategies based on generalized linear models. Although the randomization probabilities are known, we consider estimated weights in which the randomization probabilities are replaced by their empirical estimates and prove that the resulting weighted GEE estimator is more efficient than the estimators with true weights. The variance of the weighted GEE estimator is estimated by an empirical sandwich estimator. The time variable in the model can be linear, piecewise linear, or more complicated forms. This provides more flexibility that is important because, in the adaptive treatment setting, the treatment changes over time and, hence, a single linear trend over the whole period of study may not be practical. Simulation results show that the weighted GEE estimators of regression coefficients are consistent regardless of the specification of the correlation structure of the longitudinal outcomes. The weighted GEE method is then applied in analyzing data from the Clinical Antipsychotic Trials of Intervention Effectiveness. Copyright © 2016 John Wiley & Sons, Ltd.

Authors
Li, Z
MLA Citation
Li, Z. "Comparison of adaptive treatment strategies based on longitudinal outcomes in sequential multiple assignment randomized trials." Statistics in medicine 36.3 (February 2017): 403-415.
PMID
27646957
Source
epmc
Published In
Statistics in Medicine
Volume
36
Issue
3
Publish Date
2017
Start Page
403
End Page
415
DOI
10.1002/sim.7136

Outcomes of Maintenance Therapy with Bortezomib after Autologous Stem Cell Transplantation for Patients with Multiple Myeloma.

Comprehensive recommendations for maintenance therapy after autologous stem cell transplantation (ASCT) for patients with multiple myeloma (MM) have yet to be defined. Bortezomib has been utilized as maintenance therapy after ASCT, but data attesting to the safety and efficacy of this agent compared with lenalidomide in the post-ASCT setting are limited. Therefore, we retrospectively analyzed the outcomes of 102 patients with MM who received maintenance therapy with bortezomib after ASCT at Duke University's adult bone marrow transplant clinic between 2005 and 2015. Maintenance with bortezomib was initiated between 60 and 90 days after ASCT as a single agent 1.3 mg/m2 once every 2 weeks (n = 92) or in combination with lenalidomide (10 mg/day) (n = 10). The median age at ASCT was 64 (range, 31 to 78). Of the 99 patients with molecular data available, 42% had high-risk cytogenetics (including d17p, t(4;14), +1q, and t(14;16) by fluorescein in situ hybridization). Overall, 46% of patients experienced side effects from maintenance therapy, with 31% of all patients experiencing peripheral neuropathy. In total, 2% of patients required discontinuation of bortezomib maintenance because of adverse events. No secondary malignancies were reported from the therapy. The median progression-free survival (PFS) for patients receiving maintenance therapy with bortezomib after ASCT was 36.5 months (95% confidence interval [CI], 21.3 to not available) and median overall survival was 72.7 months (95% CI, 63.9 to not available). The PFS of patients with high-risk cytogenetics was not statistically significantly different from those with standard-risk cytogenetics, suggesting that maintenance with bortezomib may help overcome the impact of high-risk cytogenetics on early progression. These results indicate that maintenance therapy with bortezomib represents a safe, well-tolerated, and efficacious option for patients with high-risk cytogenetics, renal insufficiency, an inability to tolerate lenalidomide, or a previous history of another cancer.

Authors
Sivaraj, D; Green, MM; Li, Z; Sung, AD; Sarantopoulos, S; Kang, Y; Long, GD; Horwitz, ME; Lopez, RD; Sullivan, KM; Rizzieri, DA; Chao, NJ; Gasparetto, C
MLA Citation
Sivaraj, D, Green, MM, Li, Z, Sung, AD, Sarantopoulos, S, Kang, Y, Long, GD, Horwitz, ME, Lopez, RD, Sullivan, KM, Rizzieri, DA, Chao, NJ, and Gasparetto, C. "Outcomes of Maintenance Therapy with Bortezomib after Autologous Stem Cell Transplantation for Patients with Multiple Myeloma." Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 23.2 (February 2017): 262-268.
PMID
27856369
Source
epmc
Published In
Biology of Blood and Marrow Transplantation
Volume
23
Issue
2
Publish Date
2017
Start Page
262
End Page
268
DOI
10.1016/j.bbmt.2016.11.010

Semiparametric single-index model for estimating optimal individualized treatment strategy

© 2017, Institute of Mathematical Statistics. All Rights Reserved.Different from the standard treatment discovery framework which is used for finding single treatments for a homogenous group of patients, personalized medicine involves finding therapies that are tailored to each individual in a heterogeneous group. In this paper, we propose a new semiparametric additive single-index model for estimating individualized treatment strategy. The model assumes a flexible and nonparametric link function for the interaction between treatment and predictive covariates. We estimate the rule via monotone B-splines and establish the asymptotic properties of the estimators. Both simulations and an real data application demonstrate that the proposed method has a competitive performance.

Authors
Song, R; Luo, S; Zeng, D; Zhang, HH; Lu, W; Li, Z
MLA Citation
Song, R, Luo, S, Zeng, D, Zhang, HH, Lu, W, and Li, Z. "Semiparametric single-index model for estimating optimal individualized treatment strategy." Electronic Journal of Statistics 11.1 (January 1, 2017): 364-384.
Source
scopus
Published In
Electronic Journal of Statistics
Volume
11
Issue
1
Publish Date
2017
Start Page
364
End Page
384
DOI
10.1214/17-EJS1226

Plerixafor (a CXCR4 antagonist) following myeloablative allogeneic hematopoietic stem cell transplantation enhances hematopoietic recovery.

The binding of CXCR4 with its ligand (stromal-derived factor-1) maintains hematopoietic stem/progenitor cells (HSPCs) in a quiescent state. We hypothesized that blocking CXCR4/SDF-1 interaction after hematopoietic stem cell transplantation (HSCT) promotes hematopoiesis by inducing HSC proliferation.We conducted a phase I/II trial of plerixafor on hematopoietic cell recovery following myeloablative allogeneic HSCT. Patients with hematologic malignancies receiving myeloablative conditioning were enrolled. Plerixafor 240 μg/kg was administered subcutaneously every other day beginning day +2 until day +21 or until neutrophil recovery. The primary efficacy endpoints of the study were time to absolute neutrophil count >500/μl and platelet count >20,000/μl. The cumulative incidence of neutrophil and platelet engraftment of the study cohort was compared to that of a cohort of 95 allogeneic peripheral blood stem cell transplant recipients treated during the same period of time and who received similar conditioning and graft-versus-host disease prophylaxis.Thirty patients received plerixafor following peripheral blood stem cell (n = 28) (PBSC) or bone marrow (n = 2) transplantation. Adverse events attributable to plerixafor were mild and indistinguishable from effects of conditioning. The kinetics of neutrophil and platelet engraftment, as demonstrated by cumulative incidence, from the 28 study subjects receiving PBSC showed faster neutrophil (p = 0.04) and platelet recovery >20 K (p = 0.04) compared to the controls.Our study demonstrated that plerixafor can be given safely following myeloablative HSCT. It provides proof of principle that blocking CXCR4 after HSCT enhances hematopoietic recovery. Larger, confirmatory studies in other settings are warranted.ClinicalTrials.gov NCT01280955.

Authors
Green, MMB; Chao, N; Chhabra, S; Corbet, K; Gasparetto, C; Horwitz, A; Li, Z; Venkata, JK; Long, G; Mims, A; Rizzieri, D; Sarantopoulos, S; Stuart, R; Sung, AD; Sullivan, KM; Costa, L; Horwitz, M; Kang, Y
MLA Citation
Green, MMB, Chao, N, Chhabra, S, Corbet, K, Gasparetto, C, Horwitz, A, Li, Z, Venkata, JK, Long, G, Mims, A, Rizzieri, D, Sarantopoulos, S, Stuart, R, Sung, AD, Sullivan, KM, Costa, L, Horwitz, M, and Kang, Y. "Plerixafor (a CXCR4 antagonist) following myeloablative allogeneic hematopoietic stem cell transplantation enhances hematopoietic recovery." Journal of hematology & oncology 9.1 (August 17, 2016): 71-.
PMID
27535663
Source
epmc
Published In
Journal of Hematology and Oncology
Volume
9
Issue
1
Publish Date
2016
Start Page
71
DOI
10.1186/s13045-016-0301-2

Rad18 confers hematopoietic progenitor cell DNA damage tolerance independently of the Fanconi Anemia pathway in vivo.

In cultured cancer cells the E3 ubiquitin ligase Rad18 activates Trans-Lesion Synthesis (TLS) and the Fanconi Anemia (FA) pathway. However, physiological roles of Rad18 in DNA damage tolerance and carcinogenesis are unknown and were investigated here. Primary hematopoietic stem and progenitor cells (HSPC) co-expressed RAD18 and FANCD2 proteins, potentially consistent with a role for Rad18 in FA pathway function during hematopoiesis. However, hematopoietic defects typically associated with fanc-deficiency (decreased HSPC numbers, reduced engraftment potential of HSPC, and Mitomycin C (MMC) -sensitive hematopoiesis), were absent in Rad18(-/-) mice. Moreover, primary Rad18(-/-) mouse embryonic fibroblasts (MEF) retained robust Fancd2 mono-ubiquitination following MMC treatment. Therefore, Rad18 is dispensable for FA pathway activation in untransformed cells and the Rad18 and FA pathways are separable in hematopoietic cells. In contrast with responses to crosslinking agents, Rad18(-/-) HSPC were sensitive to in vivo treatment with the myelosuppressive agent 7,12 Dimethylbenz[a]anthracene (DMBA). Rad18-deficient fibroblasts aberrantly accumulated DNA damage markers after DMBA treatment. Moreover, in vivo DMBA treatment led to increased incidence of B cell malignancy in Rad18(-/-) mice. These results identify novel hematopoietic functions for Rad18 and provide the first demonstration that Rad18 confers DNA damage tolerance and tumor-suppression in a physiological setting.

Authors
Yang, Y; Poe, JC; Yang, L; Fedoriw, A; Desai, S; Magnuson, T; Li, Z; Fedoriw, Y; Araki, K; Gao, Y; Tateishi, S; Sarantopoulos, S; Vaziri, C
MLA Citation
Yang, Y, Poe, JC, Yang, L, Fedoriw, A, Desai, S, Magnuson, T, Li, Z, Fedoriw, Y, Araki, K, Gao, Y, Tateishi, S, Sarantopoulos, S, and Vaziri, C. "Rad18 confers hematopoietic progenitor cell DNA damage tolerance independently of the Fanconi Anemia pathway in vivo." Nucleic acids research 44.9 (May 2016): 4174-4188.
Website
http://hdl.handle.net/10161/12561
PMID
26883629
Source
epmc
Published In
Nucleic Acids Research
Volume
44
Issue
9
Publish Date
2016
Start Page
4174
End Page
4188
DOI
10.1093/nar/gkw072

Fitting Cox Models with Doubly Censored Data Using Spline-Based Sieve Marginal Likelihood

Authors
Li, Z; Owzar, K
MLA Citation
Li, Z, and Owzar, K. "Fitting Cox Models with Doubly Censored Data Using Spline-Based Sieve Marginal Likelihood." Scandinavian Journal of Statistics 43.2 (2016): 476-486.
PMID
27239090
Source
manual
Published In
Scandinavian Journal of Statistics
Volume
43
Issue
2
Publish Date
2016
Start Page
476
End Page
486
DOI
10.1111/sjos.12186

Targeting the Human Notch 2-BCR Axis: A Driver of B-Cell Hyper-Responsiveness in Active Chronic Graft-Versus Host Disease (cGVHD)

Authors
Poe, JC; Jia, W; Li, Z; Hakim, FT; Pavletic, SZ; Rose, JJ; Rizzieri, DA; Yang, Y; Chen, BJ; Green, M; Anand, S; Siebel, CW; Maillard, I; Chao, NJ; Sarantopoulos, S
MLA Citation
Poe, JC, Jia, W, Li, Z, Hakim, FT, Pavletic, SZ, Rose, JJ, Rizzieri, DA, Yang, Y, Chen, BJ, Green, M, Anand, S, Siebel, CW, Maillard, I, Chao, NJ, and Sarantopoulos, S. "Targeting the Human Notch 2-BCR Axis: A Driver of B-Cell Hyper-Responsiveness in Active Chronic Graft-Versus Host Disease (cGVHD)." December 3, 2015.
Source
wos-lite
Published In
Blood
Volume
126
Issue
23
Publish Date
2015

Regulation of T cell function by microRNA-720.

Chronic hepatitis B virus (HBV) infection is a major global health burden. Functional exhaustion and numerical reduction of HBV-specific cytotoxic T lymphocytes (CTLs) in the liver and peripheral blood limit anti-HBV CTL activity in patients with chronic HBV infection (CHB). However, the ongoing anti-HBV CD8(+) T cell responses in the lymphoid organs are largely unknown due to the infeasibility of obtaining lymphoid organs from CHB patients. Here we demonstrate that the percentage of HBV-specific CD8(+) T cells is higher in the spleen of CHB patients than that from peripheral blood and liver. Although they do respond to TCR stimulation and produce IFNγ, the cells proliferate poorly. Furthermore, miR-720 expression is upregulated in HBV-specific CD8(+) T cells. Overexpression of miR-720 in primary human CD8(+) T cells inhibits TCR stimulation-induced proliferation. We also demonstrate that TGFβ sustains miR-720 upregulation after TCR stimulation, and blood TGFβ levels are associated with the outcome of type I interferon treatment of CHB patients. Thus, therapies targeting miR-720 may help restore impaired immunity in CHB patients.

Authors
Wang, Y; Zhang, Z; Ji, D; Chen, G-F; Feng, X; Gong, L-L; Guo, J; Li, Z-W; Chen, C-F; Zhao, B-B; Li, Z-G; Li, Q-J; Yan, H-P; Sempowski, G; Wang, F-S; He, Y-W
MLA Citation
Wang, Y, Zhang, Z, Ji, D, Chen, G-F, Feng, X, Gong, L-L, Guo, J, Li, Z-W, Chen, C-F, Zhao, B-B, Li, Z-G, Li, Q-J, Yan, H-P, Sempowski, G, Wang, F-S, and He, Y-W. "Regulation of T cell function by microRNA-720." Scientific reports 5 (July 22, 2015): 12159-.
PMID
26199080
Source
epmc
Published In
Scientific Reports
Volume
5
Publish Date
2015
Start Page
12159
DOI
10.1038/srep12159

Cyclophosphamide-based hematopoietic stem cell mobilization before autologous stem cell transplantation in newly diagnosed multiple myeloma.

High-dose cyclophosphamide (Cy) is frequently employed for peripheral blood mobilization of hematopoietic stem cells before high-dose chemotherapy with autologous stem cell transplantation (ASCT) in multiple myeloma (MM). The benefit of mobilization with Cy over filgrastim (granulocyte colony-stimulating factor; G-CSF) alone is unclear. Between 2000 and 2008, 167 patients with newly diagnosed MM underwent single ASCT after melphalan conditioning at our institution. Seventy-three patients were mobilized with G-CSF alone, and 94 patients with Cy plus G-CSF (Cy+G-CSF). We retrospectively analyzed Cy's impact on both toxicity and efficacy. Mobilization efficiency was augmented by Cy; a mean total of 12 versus 5.8 × 10(6) CD34+ cells/kg were collected from patients mobilized with Cy+G-CSF versus G-CSF, respectively, (P < 0.01), over a mean of 1.6 versus 2.2 days of peripheral blood apheresis (p = 0.001). Mobilization-related toxicity was also, however, augmented by Cy; 14% of Cy+G-CSF patients were hospitalized because of complications versus none receiving G-CSF (P < 0.0001). Toxicity, including death, related to ASCT was similar between cohorts. Regarding long-term outcomes, multivariate analysis revealed no difference for Cy+G-CSF versus G-CSF (hazard ratio 0.8 for event-free survival [95% confidence interval {CI} 0.57-1.25] and 0.96 for overall survival [95% CI 0.61-1.54]). In summary, we show that mobilization with Cy increases toxicity without positively impacting long-term outcomes in MM. Our findings place into question Cy's benefit as a routine component of stem cell mobilization regimens in MM. Randomized trials are needed to elucidate the risks and benefits of Cy more definitively.

Authors
Tuchman, SA; Bacon, WA; Huang, L-W; Long, G; Rizzieri, D; Horwitz, M; Chute, JP; Sullivan, K; Morris Engemann, A; Yopp, A; Li, Z; Corbet, K; Chao, N; Gasparetto, C
MLA Citation
Tuchman, SA, Bacon, WA, Huang, L-W, Long, G, Rizzieri, D, Horwitz, M, Chute, JP, Sullivan, K, Morris Engemann, A, Yopp, A, Li, Z, Corbet, K, Chao, N, and Gasparetto, C. "Cyclophosphamide-based hematopoietic stem cell mobilization before autologous stem cell transplantation in newly diagnosed multiple myeloma." Journal of clinical apheresis 30.3 (June 2015): 176-182.
PMID
25293363
Source
epmc
Published In
Journal of Clinical Apheresis
Volume
30
Issue
3
Publish Date
2015
Start Page
176
End Page
182
DOI
10.1002/jca.21360

Administration of Plerixafor (a CXCR4 antagonist) Following Myeloablative Allogeneic Hematopoietic Stem Cell Transplantation Enhances Platelet Recovery in a Phase I/II Trial

Authors
Green, MMB; Horwitz, ME; Kang, Y; Chao, NJ; Long, GD; Rizzieri, D; Gasparetto, C; Sung, AD; Sarantopoulos, S; Li, Z; Corbet, K; Riggan-Stuelke, E; Sullivan, K; Wilson, B; Chhabra, S; Costa, LV; Mims, A; Stuart, R
MLA Citation
Green, MMB, Horwitz, ME, Kang, Y, Chao, NJ, Long, GD, Rizzieri, D, Gasparetto, C, Sung, AD, Sarantopoulos, S, Li, Z, Corbet, K, Riggan-Stuelke, E, Sullivan, K, Wilson, B, Chhabra, S, Costa, LV, Mims, A, and Stuart, R. "Administration of Plerixafor (a CXCR4 antagonist) Following Myeloablative Allogeneic Hematopoietic Stem Cell Transplantation Enhances Platelet Recovery in a Phase I/II Trial." February 2015.
Source
wos-lite
Published In
Biology of Blood and Marrow Transplantation
Volume
21
Issue
2
Publish Date
2015
Start Page
S31
End Page
S32

Utilization of the NIH Consensus Guidelines Improves the Diagnostic Accuracy of Gastrointestinal Graft Versus Host Disease: A Five-Year Retrospective Study

Authors
Detweiler, C; Shealy, M; Sung, A; Wild, D; Poleski, M; Balmadrid, B; Cirrincione, C; Li, Z; Sullivan, K; Cardona, D
MLA Citation
Detweiler, C, Shealy, M, Sung, A, Wild, D, Poleski, M, Balmadrid, B, Cirrincione, C, Li, Z, Sullivan, K, and Cardona, D. "Utilization of the NIH Consensus Guidelines Improves the Diagnostic Accuracy of Gastrointestinal Graft Versus Host Disease: A Five-Year Retrospective Study." February 2015.
Source
wos-lite
Published In
Laboratory Investigation
Volume
95
Publish Date
2015
Start Page
157A
End Page
157A

Late Gastrointestinal Complications of Allogeneic Hematopoietic Stem Cell Transplantation

Authors
Sung, AD; Cardona, D; Rowe, K; Mehdikhani, H; Detweiler, C; Shealy, M; Wild, D; Poleski, M; Cirrincione, C; Li, Z; Chao, NJ; Sullivan, K
MLA Citation
Sung, AD, Cardona, D, Rowe, K, Mehdikhani, H, Detweiler, C, Shealy, M, Wild, D, Poleski, M, Cirrincione, C, Li, Z, Chao, NJ, and Sullivan, K. "Late Gastrointestinal Complications of Allogeneic Hematopoietic Stem Cell Transplantation." February 2015.
Source
wos-lite
Published In
Biology of Blood and Marrow Transplantation
Volume
21
Issue
2
Publish Date
2015
Start Page
S314
End Page
S315

Utilization of the NIH Consensus Guidelines Improves the Diagnostic Accuracy of Gastrointestinal Graft Versus Host Disease: A Five-Year Retrospective Study

Authors
Detweiler, C; Shealy, M; Sung, A; Wild, D; Poleski, M; Balmadrid, B; Cirrincione, C; Li, Z; Sullivan, K; Cardona, D
MLA Citation
Detweiler, C, Shealy, M, Sung, A, Wild, D, Poleski, M, Balmadrid, B, Cirrincione, C, Li, Z, Sullivan, K, and Cardona, D. "Utilization of the NIH Consensus Guidelines Improves the Diagnostic Accuracy of Gastrointestinal Graft Versus Host Disease: A Five-Year Retrospective Study." MODERN PATHOLOGY 28 (February 2015): 157A-157A.
Source
wos-lite
Published In
Modern Pathology
Volume
28
Publish Date
2015
Start Page
157A
End Page
157A

A global logrank test for adaptive treatment strategies based on observational studies

In studying adaptive treatment strategies, a natural question that is of paramount interest is whether there is any significant difference among all possible treatment strategies. When the outcome variable of interest is time-to-event, we propose an inverse probability weighted logrank test for testing the equivalence of a fixed set of pre-specified adaptive treatment strategies based on data from an observational study. The weights take into account both the possible selection bias in an observational study and the fact that the same subject may be consistent with more than one treatment strategy. The asymptotic distribution of the weighted logrank statistic under the null hypothesis is obtained. We show that, in an observational study where the treatment selection probabilities need to be estimated, the estimation of these probabilities does not have an effect on the asymptotic distribution of the weighted logrank statistic, as long as the estimation of the parameters in the models for these probabilities is n-consistent. Finite sample performance of the test is assessed via a simulation study. We also show in the simulation that the test can be pretty robust to misspecification of the models for the probabilities of treatment selection. The method is applied to analyze data on antidepressant adherence time from an observational database maintained at the Department of Veterans Affairs' Serious Mental Illness Treatment Research and Evaluation Center. © 2013 John Wiley & Sons, Ltd.

Authors
Li, Z; Valenstein, M; Pfeiffer, P; Ganoczy, D
MLA Citation
Li, Z, Valenstein, M, Pfeiffer, P, and Ganoczy, D. "A global logrank test for adaptive treatment strategies based on observational studies." Statistics in Medicine 33.5 (February 28, 2014): 760-771.
Source
scopus
Published In
Statistics in Medicine
Volume
33
Issue
5
Publish Date
2014
Start Page
760
End Page
771
DOI
10.1002/sim.5987

Reduced-intensity allogeneic transplantation using alemtuzumab from HLA-matched related, unrelated, or haploidentical related donors for patients with hematologic malignancies.

We present a comparative study on 124 patients with hematologic malignancies who had undergone reduced-intensity conditioning and then received a transplant from an HLA-matched related (MRD), an HLA-matched unrelated (MUD), or an HLA-haploidentical related (HAPLO) donor. The conditioning regimen, which consisted of fludarabine, melphalan or busulfan, and alemtuzumab was administered to patients with lymphoid (n = 62) or myeloid disease (n = 62). Mycophenolate mofetil was used as prophylaxis for graft-versus-host disease (GVHD), and 38, 58, and 33 patients received transplants from MRD, MUD, and HAPLO donors, respectively. Only 2 patients experienced primary graft failure (GF) after melphalan-based regimen, whereas 8 of the 17 patients who received a transplant from HAPLO donors experienced a primary GF after busulfan-based regimen. The cumulative incidence of grade III to IV acute GVHD in engrafted patients who had received transplants from MRD, MUD, or HAPLO donors was 3%, 11%, and 27%, respectively, and the 2-year overall survival (OS) rates were 51%, 22%, and 23%, respectively. According to multivariate analysis, transplantation from either MUD or HAPLO donors compared with MRD were adverse factors that affected the OS (P = .006 and P = .002, respectively). In conclusion, the reduced-intensity regimen that included fludarabine, busulfan, or melphalan and alemtuzumab using only mycophenolate mofetil as the GVHD prophylaxis conferred favorable outcomes in the MRD group but lower survival rates in the MUD and HAPLO groups. The busulfan-based regimen led to a high incidence of GF in the HAPLO group, suggesting the need for modification or intensification of immunosuppression.

Authors
Kanda, J; Long, GD; Gasparetto, C; Horwitz, ME; Sullivan, KM; Chute, JP; Morris, A; Shafique, M; Li, Z; Chao, NJ; Rizzieri, DA
MLA Citation
Kanda, J, Long, GD, Gasparetto, C, Horwitz, ME, Sullivan, KM, Chute, JP, Morris, A, Shafique, M, Li, Z, Chao, NJ, and Rizzieri, DA. "Reduced-intensity allogeneic transplantation using alemtuzumab from HLA-matched related, unrelated, or haploidentical related donors for patients with hematologic malignancies." Biol Blood Marrow Transplant 20.2 (February 2014): 257-263.
PMID
24269380
Source
pubmed
Published In
Biology of Blood and Marrow Transplantation
Volume
20
Issue
2
Publish Date
2014
Start Page
257
End Page
263
DOI
10.1016/j.bbmt.2013.11.010

Plasma microRNA signature as a noninvasive biomarker for acute graft-versus-host disease.

Acute graft-versus-host disease (aGVHD) is the leading cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). Approximately 35% to 50% of HCT recipients develop aGVHD; however, there are no validated diagnostic and predictive blood biomarkers for aGVHD in clinical use. Here, we show that plasma samples from aGVHD patients have a distinct microRNA (miRNA) expression profile. We found that 6 miRNAs (miR-423, miR-199a-3p, miR-93*, miR-377, miR-155, and miR-30a) were significantly upregulated in the plasma of aGVHD patients (n = 116) when compared with non-GVHD patients (n = 52) in training and validation phases. We have developed a model including 4 miRNAs (miR-423, miR-199a-3p, miR-93*, and miR-377) that can predict the probability of aGVHD with an area under the curve of 0.80. Moreover, these elevated miRNAs were detected before the onset of aGVHD (median = 16 days before diagnosis). In addition, the levels of these miRNAs were positively associated with aGVHD severity, and high expression of the miRNA panel was associated with poor overall survival. Furthermore, the miRNA signature for aGVHD was not detected in the plasma of lung transplant or nontransplant sepsis patients. Our results have identified a specific plasma miRNA signature that may serve as an independent biomarker for the prediction, diagnosis, and prognosis of aGVHD.

Authors
Xiao, B; Wang, Y; Li, W; Baker, M; Guo, J; Corbet, K; Tsalik, EL; Li, Q-J; Palmer, SM; Woods, CW; Li, Z; Chao, NJ; He, Y-W
MLA Citation
Xiao, B, Wang, Y, Li, W, Baker, M, Guo, J, Corbet, K, Tsalik, EL, Li, Q-J, Palmer, SM, Woods, CW, Li, Z, Chao, NJ, and He, Y-W. "Plasma microRNA signature as a noninvasive biomarker for acute graft-versus-host disease." Blood 122.19 (November 7, 2013): 3365-3375.
PMID
24041574
Source
pubmed
Published In
Blood
Volume
122
Issue
19
Publish Date
2013
Start Page
3365
End Page
3375
DOI
10.1182/blood-2013-06-510586

Insulin-like growth factor 1 mitigates hematopoietic toxicity after lethal total body irradiation.

PURPOSE: To investigate whether and how insulin-like growth factor 1 (IGF-1) mitigates hematopoietic toxicity after total body irradiation. METHODS AND MATERIALS: BALB/c mice were irradiated with a lethal dose of radiation (7.5 Gy) and treated with IGF-1 at a dose of 100 μg/dose intravenously once a day for 5 consecutive days starting within 1 hour after exposure. Survival and hematopoietic recovery were monitored. The mechanisms by which IGF-1 promotes hematopoietic recovery were also studied by use of an in vitro culture system. RESULTS: IGF-1 protected 8 of 20 mice (40%) from lethal irradiation, whereas only 2 of 20 mice (10%) in the saline control group survived for more than 100 days after irradiation. A single dose of IGF-1 (500 μg) was as effective as daily dosing for 5 days. Positive effects were noted even when the initiation of treatment was delayed as long as 6 hours after irradiation. In comparison with the saline control group, treatment with IGF-1 significantly accelerated the recovery of both platelets and red blood cells in peripheral blood, total cell numbers, hematopoietic stem cells, and progenitor cells in the bone marrow when measured at day 14 after irradiation. IGF-1 protected both hematopoietic stem cells and progenitor cells from radiation-induced apoptosis and cell death. In addition, IGF-1 was able to facilitate the proliferation and differentiation of nonirradiated and irradiated hematopoietic progenitor cells. CONCLUSIONS: IGF-1 mitigates radiation-induced hematopoietic toxicity through protecting hematopoietic stem cells and progenitor cells from apoptosis and enhancing proliferation and differentiation of the surviving hematopoietic progenitor cells.

Authors
Zhou, D; Deoliveira, D; Kang, Y; Choi, SS; Li, Z; Chao, NJ; Chen, BJ
MLA Citation
Zhou, D, Deoliveira, D, Kang, Y, Choi, SS, Li, Z, Chao, NJ, and Chen, BJ. "Insulin-like growth factor 1 mitigates hematopoietic toxicity after lethal total body irradiation." Int J Radiat Oncol Biol Phys 85.4 (March 15, 2013): 1141-1148.
PMID
23021438
Source
pubmed
Published In
International Journal of Radiation: Oncology - Biology - Physics
Volume
85
Issue
4
Publish Date
2013
Start Page
1141
End Page
1148
DOI
10.1016/j.ijrobp.2012.08.014

Re-induction therapy decisions based on day 14 bone marrow biopsy in acute myeloid leukemia.

PURPOSE: The decision to re-induce patients with acute myeloid leukemia (AML) based on results of the day 14 bone marrow (BM) biopsy is variable and lacks evidence based data. The aim of our review was to evaluate the accuracy of a day 14 BM biopsy in determining the need for re-induction chemotherapy. METHODS: Seventy-four patients with newly diagnosed de novo AML treated with induction chemotherapy were retrospectively reviewed for the purpose of evaluating treatment decisions and outcomes based on their day 14 BM biopsy. Response to therapy in this analysis was based on morphology alone. RESULTS: Of the 74 patients undergoing standard induction, 45 patients (61%) had no evidence of leukemia on their day 14 BM biopsy. Eighteen patients (24%) had definitive residual disease (RD), and 11 patient's (15%) were classified as indeterminate response (IR). Fifteen patients with RD and one with IR underwent re-induction chemotherapy. However, thirteen patients (3 RD and 10 IR) were observed until count recovery without any re-induction therapy. Eleven of these 13 patients who were observed eventually attained a morphologic complete remission (CR), including two patients with RD. CONCLUSIONS: A day 14 BM biopsy may have suboptimal sensitivity for the detection of residual leukemia. Some patients with an IR on day 14 may not require re-induction chemotherapy, but instead, may benefit from careful observation until count recovery to avoid the mortality and morbidity associated with re-induction chemotherapy.

Authors
Morris, TA; DeCastro, CM; Diehl, LF; Gockerman, JP; Lagoo, AS; Li, Z; Moore, JO; Rizzieri, DA; Rao, AV
MLA Citation
Morris, TA, DeCastro, CM, Diehl, LF, Gockerman, JP, Lagoo, AS, Li, Z, Moore, JO, Rizzieri, DA, and Rao, AV. "Re-induction therapy decisions based on day 14 bone marrow biopsy in acute myeloid leukemia." Leuk Res 37.1 (January 2013): 28-31.
PMID
23046833
Source
pubmed
Published In
Leukemia Research: clinical and laboratory studies
Volume
37
Issue
1
Publish Date
2013
Start Page
28
End Page
31
DOI
10.1016/j.leukres.2012.09.016

Upregulation of IL-1β, IL-6, and CCL-2 by a novel mouse model of pancreatic ischemia-reperfusion injury

BACKGROUND: Little is known about the immunologic events surrounding pancreatic ischemia-reperfusion injury (IRI) because of a lack of established experimental models. The purpose of this study was to develop a mouse model for pancreatic IRI to serve as a basis for the immunologic characterization of pancreatic organ damage at transplantation. METHODS: Reversible ischemia was surgically induced by vascular isolation of the distal pancreas for 0, 10, 20, or 30 min. Mice receiving laparotomy without clamping served as sham-operated controls. After reperfusion, mice were serially assayed for biochemical and histologic evidence of inflammation, proinflammatory cytokine and chemokine production, and inflammatory gene upregulation. RESULTS: After induction of pancreatic IRI, serum amylase and lactate dehydrogenase peaked at 6 hr and returned to baseline by 120 hr after injury in all groups. Mice undergoing 30 min of IRI demonstrated the greatest biochemical evidence of inflammation. Histologic scoring similarly demonstrated marked inflammation in mice subjected to 30-min IRI compared with controls. Serum cytokine/chemokine analysis demonstrated significant upregulation of granulocyte colony-stimulating factor, interferon γ, tumor necrosis factor α, interleukin (IL)-2, IL-1β, IL-6, chemokine (C-C motif) ligand-2, chemokine (C-C motif) ligand-5, chemokine (C-X-C motif) ligand-1, and macrophage inflammatory protein 2. A similar upregulation of ccl2, il1b, il6, fos, hspa1a, hspd1, and cd14 gene expression was detected by real-time polymerase chain reaction analysis of pancreatic tissue. CONCLUSIONS: This novel model of distal pancreatic IRI in the mouse demonstrates time-limited pancreatic inflammation and injury by histologic and biochemical indices. Inflammation may be, in part, a result of the immunologic effects of IL-1β, IL-6, and CCL-2. This model provides a method by which immunologic mechanisms of pancreatic IRI can be elucidated. Copyright © 2013 by Lippincott Williams & Wilkins.

Authors
Lunsford, KE; Baird, BJ; Sempowski, GD; Cardona, DM; Li, Z; Weinhold, KJ; Sudan, DL; Brennan, TV
MLA Citation
Lunsford, KE, Baird, BJ, Sempowski, GD, Cardona, DM, Li, Z, Weinhold, KJ, Sudan, DL, and Brennan, TV. "Upregulation of IL-1β, IL-6, and CCL-2 by a novel mouse model of pancreatic ischemia-reperfusion injury." Transplantation 95.8 (2013): 1000-1007.
Source
scival
Published In
Transplantation
Volume
95
Issue
8
Publish Date
2013
Start Page
1000
End Page
1007
DOI
10.1097/TP.0b013e318286483a

Heparan sulfate, an endogenous TLR4 agonist, promotes acute GVHD after allogeneic stem cell transplantation.

Graft-versus-host disease (GVHD) remains the most common cause of nonrelapse-related morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although T-cell depletion and intensive immunosuppression are effective in the control of GVHD, they are often associated with higher rates of infection and tumor recurrence. In this study, we showed that heparan sulfate (HS), an extracellular matrix component, can activate Toll-like receptor 4 on dendritic cells in vitro, leading to the enhancement of dendritic cell maturation and alloreactive T-cell responses. We further demonstrated in vivo that serum HS levels were acutely elevated at the onset of clinical GVHD in mice after allo-HSCT. Treatment with the serine protease inhibitor α1-antitrypsin decreased serum levels of HS, leading to a reduction in alloreactive T-cell responses and GVHD severity. Conversely, an HS mimetic that increased serum HS levels accelerated GVHD. In addition, in patients undergoing allo-HSCT for hematologic malignancies, serum HS levels were elevated and correlated with the severity of GVHD. These results identify a critical role for HS in promoting acute GVHD after allo-HSCT, and they suggest that modulation of HS release may have therapeutic potential for the control of clinical GVHD.

Authors
Brennan, TV; Lin, L; Huang, X; Cardona, DM; Li, Z; Dredge, K; Chao, NJ; Yang, Y
MLA Citation
Brennan, TV, Lin, L, Huang, X, Cardona, DM, Li, Z, Dredge, K, Chao, NJ, and Yang, Y. "Heparan sulfate, an endogenous TLR4 agonist, promotes acute GVHD after allogeneic stem cell transplantation." Blood 120.14 (October 4, 2012): 2899-2908.
PMID
22760779
Source
pubmed
Published In
Blood
Volume
120
Issue
14
Publish Date
2012
Start Page
2899
End Page
2908
DOI
10.1182/blood-2011-07-368720

Power and sample size calculations for SNP association studies with censored time-to-event outcomes.

For many clinical studies in cancer, germline DNA is prospectively collected for the purpose of discovering or validating single-nucleotide polymorphisms (SNPs) associated with clinical outcomes. The primary clinical endpoint for many of these studies are time-to-event outcomes such as time of death or disease progression which are subject to censoring mechanisms. The Cox score test can be readily employed to test the association between a SNP and the outcome of interest. In addition to the effect and sample size, and censoring distribution, the power of the test will depend on the underlying genetic risk model and the distribution of the risk allele. We propose a rigorous account for power and sample size calculations under a variety of genetic risk models without resorting to the commonly used contiguous alternative assumption. Practical advice along with an open-source software package to design SNP association studies with survival outcomes are provided.

Authors
Owzar, K; Li, Z; Cox, N; Jung, S-H
MLA Citation
Owzar, K, Li, Z, Cox, N, and Jung, S-H. "Power and sample size calculations for SNP association studies with censored time-to-event outcomes." Genet Epidemiol 36.6 (September 2012): 538-548.
PMID
22685040
Source
pubmed
Published In
Genetic Epidemiology
Volume
36
Issue
6
Publish Date
2012
Start Page
538
End Page
548
DOI
10.1002/gepi.21645

Outcomes of a 1-day nonmyeloablative salvage regimen for patients with primary graft failure after allogeneic hematopoietic cell transplantation.

Primary graft failure after allogeneic hematopoietic cell transplantation is a life-threatening complication. A shortened conditioning regimen may reduce the risk of infection and increase the chance of survival. Here, we report the outcome of 11 patients with hematologic diseases (median age, 44; range, 25-67 years, seven males) who received a 1-day reduced-intensity preparative regimen given as a re-transplantation for primary graft failure. The salvage regimen consisted of fludarabine, cyclophosphamide, alemtuzumab and TBI, all administered 1 day before re-transplantation. All patients received T-cell replete PBSCs from the same or a different haploidentical donor (n=10) or from the same matched sibling donor (n=1). Neutrophil counts promptly increased to >500/μL for 10 of the 11 patients at a median of 13 days. Of these, none developed grade III/IV acute GVHD. At present, 8 of the 11 patients are alive with a median follow-up of 11.2 months from re-transplantation and 5 of the 8 are in remission. In conclusion, this series suggests that our 1-day preparative regimen is feasible, leads to successful engraftment in a high proportion of patients, and is appropriate for patients requiring immediate re-transplantation after primary graft failure following reduced-intensity transplantation.

Authors
Kanda, J; Horwitz, ME; Long, GD; Gasparetto, C; Sullivan, KM; Chute, JP; Morris, A; Hennig, T; Li, Z; Chao, NJ; Rizzieri, DA
MLA Citation
Kanda, J, Horwitz, ME, Long, GD, Gasparetto, C, Sullivan, KM, Chute, JP, Morris, A, Hennig, T, Li, Z, Chao, NJ, and Rizzieri, DA. "Outcomes of a 1-day nonmyeloablative salvage regimen for patients with primary graft failure after allogeneic hematopoietic cell transplantation." Bone Marrow Transplant 47.5 (May 2012): 700-705.
PMID
21804612
Source
pubmed
Published In
Bone Marrow Transplantation
Volume
47
Issue
5
Publish Date
2012
Start Page
700
End Page
705
DOI
10.1038/bmt.2011.158

Phase II study of cenersen, an antisense inhibitor of p53, in combination with fludarabine, cyclophosphamide and rituximab for high-risk chronic lymphocytic leukemia.

Patients with chronic lymphocytic leukemia (CLL) with deletion or mutation of TP53 have exceedingly poor clinical outcomes. Cenersen, an oligonucleotide targeting TP53, has been shown to abrogate the activity of TP53 gain-of-function mutants and to increase sensitivity of lymphoma cells to cytotoxic chemotherapy in vitro. We combined cenersen with fludarabine, cyclophosphamide and rituximab (FCR) as treatment for patients with high-risk CLL. The purpose of this phase II study was to determine the overall response rate, response duration and toxicity of cenersen administered in combination with FCR. Twenty patients with relapsed or high-risk CLL were evaluated. Nineteen patients were previously treated. The complete response rate was 18%; the overall response rate was 53%. Median progression-free and overall survival was 5.3 and 10.6 months, respectively. The most common serious adverse events were neutropenia and thrombocytopenia. In this single arm phase II study, cenersen combined with FCR yielded clinical responses with acceptable toxicity in patients with high-risk CLL.

Authors
Lanasa, MC; Davis, PH; Datto, M; Li, Z; Gockerman, JP; Moore, JO; DeCastro, CM; Friedman, DR; Diehl, LF; Rehder, C; Cook, H; Daugherty, FJ; Matta, KMB; Weinberg, JB; Rizzieri, D
MLA Citation
Lanasa, MC, Davis, PH, Datto, M, Li, Z, Gockerman, JP, Moore, JO, DeCastro, CM, Friedman, DR, Diehl, LF, Rehder, C, Cook, H, Daugherty, FJ, Matta, KMB, Weinberg, JB, and Rizzieri, D. "Phase II study of cenersen, an antisense inhibitor of p53, in combination with fludarabine, cyclophosphamide and rituximab for high-risk chronic lymphocytic leukemia." Leuk Lymphoma 53.2 (February 2012): 218-224.
PMID
21827374
Source
pubmed
Published In
Leukemia & Lymphoma (Informa)
Volume
53
Issue
2
Publish Date
2012
Start Page
218
End Page
224
DOI
10.3109/10428194.2011.610012

Emergent anxiety after antidepressant initiation: a retrospective cohort study of Veterans Affairs Health System patients with depression.

BACKGROUND: Initiation of antidepressant treatment for depression may be associated with new onset (emergent) anxiety. OBJECTIVE: The purpose of this study was to assess demographic and clinical factors associated with emergent anxiety following a new antidepressant start among Department of Veterans Affairs (VA) Health System patients with depression. METHODS: Using a retrospective cohort design, we obtained data from 328,888 VA patients with depression who were newly prescribed 1 of the 7 most commonly used antidepressant drugs between April 1999 and September 2004 from the VA National Depression Registry. We examined the prevalence of emergent anxiety, defined as either a new anxiety diagnoses or by new antianxiety medication starts, during the 12 weeks following new antidepressant start. In multivariate analyses, we assessed the hazard ratios for emerging anxiety associated with patient characteristics and specific antidepressant agents. RESULTS: Approximately 3% of patients developed clinically significant anxiety within 12 weeks of starting an antidepressant drug regimen. Younger age (age <45 years and 45-64 years) was associated with higher risks for emergent anxiety than older age (≥65 years) (hazard ratio [HR] = 1.72 and 1.55; 95% CI, 1.59-1.85, and 1.38-1.72, respectively). Female gender was associated with higher risks than male gender (HR = 1.17; 95% CI, 1.10-1.26), and white and other races compared with black race were associated with higher risks of emergent anxiety (HR = 1.49 and 1.13; 95% CI, 1.30-1.59 and 1.04-1.23, respectively). Finally, filling antidepressant drug prescriptions in years subsequent to 1999 was associated with lower risks of emergent anxiety. CONCLUSIONS: Only a small proportion of patients developed emergent anxiety following a new antidepressant start, resulting in a new diagnosis or antianxiety medication use. Anxiety occurred more often in young adults, whites, and women.

Authors
Li, Z; Pfeiffer, PN; Hoggatt, KJ; Zivin, K; Downing, K; Ganoczy, D; Valenstein, M
MLA Citation
Li, Z, Pfeiffer, PN, Hoggatt, KJ, Zivin, K, Downing, K, Ganoczy, D, and Valenstein, M. "Emergent anxiety after antidepressant initiation: a retrospective cohort study of Veterans Affairs Health System patients with depression." Clin Ther 33.12 (December 2011): 1985-1992.e1.
PMID
22177372
Source
pubmed
Published In
Clinical Therapeutics: the international peer-reviewed journal of drug therapy
Volume
33
Issue
12
Publish Date
2011
Start Page
1985
End Page
1992.e1
DOI
10.1016/j.clinthera.2011.11.010

High Complete Response Rates with Dose Dense/Dose Intense Chemotherapy Plus Radioimmunotherapy in High Risk Diffuse Large B Cell and Mantle Cell Lymphoma

Authors
Beaven, AW; Rizzieri, DA; Powell, Z; Li, Z; Alton, P; Warzecho, J; Diehl, LF; Moore, JO; III, DCCM; Gockerman, JP
MLA Citation
Beaven, AW, Rizzieri, DA, Powell, Z, Li, Z, Alton, P, Warzecho, J, Diehl, LF, Moore, JO, III, DCCM, and Gockerman, JP. "High Complete Response Rates with Dose Dense/Dose Intense Chemotherapy Plus Radioimmunotherapy in High Risk Diffuse Large B Cell and Mantle Cell Lymphoma." November 18, 2011.
Source
wos-lite
Published In
Blood
Volume
118
Issue
21
Publish Date
2011
Start Page
1152
End Page
1152

High Dose BCNU/Melphalan Preparative Regimen Doubles Event Free Survival of Myeloma Patients Undergoing Autologous Transplantation

Authors
Gasparetto, C; Bacon, WA; Doan, P; Rizzieri, DA; Horwitz, ME; Chute, JP; Sullivan, KM; Yopp, A; Li, Z; Chao, NJ; Long, GD
MLA Citation
Gasparetto, C, Bacon, WA, Doan, P, Rizzieri, DA, Horwitz, ME, Chute, JP, Sullivan, KM, Yopp, A, Li, Z, Chao, NJ, and Long, GD. "High Dose BCNU/Melphalan Preparative Regimen Doubles Event Free Survival of Myeloma Patients Undergoing Autologous Transplantation." November 18, 2011.
Source
wos-lite
Published In
Blood
Volume
118
Issue
21
Publish Date
2011
Start Page
879
End Page
879

Sample size formulae for two-stage randomized trials with survival outcomes.

Two-stage randomized trials are growing in importance in developing adaptive treatment strategies, i.e. treatment policies or dynamic treatment regimes. Usually, the first stage involves randomization to one of the several initial treatments. The second stage of treatment begins when an early nonresponse criterion or response criterion is met. In the second-stage, nonresponding subjects are re-randomized among second-stage treatments. Sample size calculations for planning these two-stage randomized trials with failure time outcomes are challenging because the variances of common test statistics depend in a complex manner on the joint distribution of time to the early nonresponse criterion or response criterion and the primary failure time outcome. We produce simple, albeit conservative, sample size formulae by using upper bounds on the variances. The resulting formulae only require the working assumptions needed to size a standard single-stage randomized trial and, in common settings, are only mildly conservative. These sample size formulae are based on either a weighted Kaplan-Meier estimator of survival probabilities at a fixed time-point or a weighted version of the log-rank test.

Authors
Li, Z; Murphy, SA
MLA Citation
Li, Z, and Murphy, SA. "Sample size formulae for two-stage randomized trials with survival outcomes." Biometrika 98.3 (September 2011): 503-518.
PMID
22363091
Source
pubmed
Published In
Biometrika
Volume
98
Issue
3
Publish Date
2011
Start Page
503
End Page
518
DOI
10.1093/biomet/asr019

Hematopoietic cell infusion for the treatment of nuclear disaster victims: new data from the Chernobyl accident.

PURPOSE: To present previously unavailable data on the use of stem cell administration to aid recovery of victims of the Chernobyl disaster. On 26 April 1986, an accident at Unit 4 of the Chernobyl Nuclear Power Plant took place during the planned test of one of the safety systems. The diagnosis of acute radiation syndrome (ARS) was confirmed in 134 individuals exposed to high levels of radiation. There were nine patients heretofore unreported in the scientific literature who underwent intraosseous injections of allogeneic bone marrow cells in Kyiv. CONCLUSIONS: Transplantation was associated with significantly shortened time to recovery of granulocyte and platelet counts in these patients. While current guidelines would certainly include the use of cytokines, these data provide an indication of the effectiveness of stem cell transplant to treat victims of radiation exposure.

Authors
Klymenko, SV; Belyi, DA; Ross, JR; Owzar, K; Jiang, C; Li, Z; N Minchenko, J; N Kovalenko, A; Bebeshko, VG; J Chao, N
MLA Citation
Klymenko, SV, Belyi, DA, Ross, JR, Owzar, K, Jiang, C, Li, Z, N Minchenko, J, N Kovalenko, A, Bebeshko, VG, and J Chao, N. "Hematopoietic cell infusion for the treatment of nuclear disaster victims: new data from the Chernobyl accident." Int J Radiat Biol 87.8 (August 2011): 846-850.
PMID
21406047
Source
pubmed
Published In
International Journal of Radiation Biology (Informa)
Volume
87
Issue
8
Publish Date
2011
Start Page
846
End Page
850
DOI
10.3109/09553002.2011.560995

Feasibility of low-dose interleukin-2 therapy following T-cell-depleted nonmyeloablative allogeneic hematopoietic stem cell transplantation from HLA-matched or -mismatched family member donors.

INTRODUCTION: High relapse rates and infections remain primary causes of failure in nonmyeloablative transplantation. Interleukin-2 (IL-2) may stimulate the immune system and improve outcomes. The primary objective of this pilot study was to evaluate the feasibility of administering IL-2 following a T-cell-depleted nonmyeloablative hematopoietic stem cell transplant. METHODS: Patients received T-cell-depleted nonmyeloablative transplant from a matched or mismatched related donor. Those with allogeneic engraftment,

Authors
Rizzieri, DA; Crout, C; Storms, R; Golob, J; Long, GD; Gasparetto, C; Sullivan, KM; Horwitz, M; Chute, J; Lagoo, AS; Morris, A; Beaven, A; Yang, Y; Peterson, B; Li, Z; Chao, NJ
MLA Citation
Rizzieri, DA, Crout, C, Storms, R, Golob, J, Long, GD, Gasparetto, C, Sullivan, KM, Horwitz, M, Chute, J, Lagoo, AS, Morris, A, Beaven, A, Yang, Y, Peterson, B, Li, Z, and Chao, NJ. "Feasibility of low-dose interleukin-2 therapy following T-cell-depleted nonmyeloablative allogeneic hematopoietic stem cell transplantation from HLA-matched or -mismatched family member donors." Cancer Invest 29.1 (January 2011): 56-61.
PMID
21166499
Source
pubmed
Published In
Cancer Investigation (Informa)
Volume
29
Issue
1
Publish Date
2011
Start Page
56
End Page
61
DOI
10.3109/07357907.2010.535055

Relative risk regression for current status data in case-cohort studies

We propose using the weighted likelihood method to fit a general relative risk regression model for the current status data with missing data as arise, for example, in case-cohort studies. The missingness probability is either known or can be reasonably estimated. Asymptotic properties of the weighted likelihood estimators are established. For the case of using estimated weights, we construct a general theorem that guarantees the asymptotic normality of the M-estimator of a finite dimensional parameter in a class of semiparametric models, where the infinite dimensional parameter is allowed to converge at a slower than parametric rate, and some other parameters in the objective function are estimated a priori. The weighted bootstrap method is employed to estimate the variances. Simulations show that the proposed method works well for finite sample sizes. A motivating example of the case-cohort study from an HIV vaccine trial is used to demonstrate the proposed method. © 2011 Statistical Society of Canada.

Authors
Li, Z; Nan, B
MLA Citation
Li, Z, and Nan, B. "Relative risk regression for current status data in case-cohort studies." Canadian Journal of Statistics 39.4 (2011): 557-577.
Source
scival
Published In
The Canadian Journal of Statistics
Volume
39
Issue
4
Publish Date
2011
Start Page
557
End Page
577
DOI
10.1002/cjs.10111

Prospective, Biological Randomized Study of T-Cell Depleted Nonmyeloablative Allogeneic Transplantation From HLA-Matched Related, Unrelated or Haploidentical Donors for Patients with Hematologic Malignancies.

Authors
Kanda, J; Long, GD; Gasparetto, C; Horwitz, ME; Sullivan, KM; Chute, JP; Morris, A; Li, Z; Chao, NJ; Rizzieri, DA
MLA Citation
Kanda, J, Long, GD, Gasparetto, C, Horwitz, ME, Sullivan, KM, Chute, JP, Morris, A, Li, Z, Chao, NJ, and Rizzieri, DA. "Prospective, Biological Randomized Study of T-Cell Depleted Nonmyeloablative Allogeneic Transplantation From HLA-Matched Related, Unrelated or Haploidentical Donors for Patients with Hematologic Malignancies." November 19, 2010.
Source
wos-lite
Published In
Blood
Volume
116
Issue
21
Publish Date
2010
Start Page
1456
End Page
1457

Construction of confidence intervals and regions for ordered binomial probabilities

In biomedical studies and other areas, there are often situations where parameters are known to be ordered. In these situations, incorporating the order restriction can produce much more efficient estimates than ignoring it. There is much research on point estimation and tests with order restrictions, but little on the construction of confidence intervals. Our particular interest is in the case where two probabilities for binomial random variables can be equal or very close to each other, where difficulty arises and the standard methods for inference no longer apply. We investigate methods for constructing confidence intervals for the ordered probabilities based on appropriate asymptotic distributions and several versions of the bootstrap. Via simulation studies we find that the usual percentile bootstrap and a parametric bootstrap with parameter shrunk to the boundary both have good finite sample properties. We further consider the construction of confidence regions for two ordered probabilities. We propose a small sample test for the probabilities and a method for constructing confidence regions by inverting this test, which yields confidence regions with good coverage rates even in very small samples. Supplemental materials for the technical results and proofs are available online. © 2010 American Statistical Association.

Authors
Li, Z; Taylor, JMG; Nan, B
MLA Citation
Li, Z, Taylor, JMG, and Nan, B. "Construction of confidence intervals and regions for ordered binomial probabilities." American Statistician 64.4 (2010): 291-298.
Source
scival
Published In
The American statistician
Volume
64
Issue
4
Publish Date
2010
Start Page
291
End Page
298
DOI
10.1198/tast.2010.09096

Weighted likelihood method for grouped survival data in case-cohort studies with application to HIV vaccine trials

Grouped failure time data arise often in HIV studies. In a recent preventive HIV vaccine efficacy trial, immune responses generated by the vaccine were measured from a case-cohort sample of vaccine recipients, who were subsequently evaluated for the study endpoint of HIV infection at prespecified follow-up visits. Gilbert et al. (2005, Journal of Infectious Diseases 191, 666-677) and Forthal et al. (2007, Journal of Immunology 178, 6596-6603) analyzed the association between the immune responses and HIV incidence with a Cox proportional hazards model, treating the HIV infection diagnosis time as a right-censored random variable. The data, however, are of the form of grouped failure time data with case-cohort covariate sampling, and we propose an inverse selection probability-weighted likelihood method for fitting the Cox model to these data. The method allows covariates to be time dependent, and uses multiple imputation to accommodate covariate data that are missing at random. We establish asymptotic properties of the proposed estimators, and present simulation results showing their good finite sample performance. We apply the method to the HIV vaccine trial data, showing that higher antibody levels are associated with a lower hazard of HIV infection. © 2008, The International Biometric Society.

Authors
Li, Z; Gilbert, P; Nan, B
MLA Citation
Li, Z, Gilbert, P, and Nan, B. "Weighted likelihood method for grouped survival data in case-cohort studies with application to HIV vaccine trials." Biometrics 64.4 (2008): 1247-1255.
PMID
19032178
Source
scival
Published In
Biometrics
Volume
64
Issue
4
Publish Date
2008
Start Page
1247
End Page
1255
DOI
10.1111/j.1541-0420.2008.00998.x

Analysis on binary responses with ordered covariates and missing data

We consider the situation of two ordered categorical variables and a binary outcome variable, where one or both of the categorical variables may have missing values. The goal is to estimate the probability of response of the outcome variable for each cell of the contingency table of categorical variables while incorporating the fact that the categorical variables are ordered. The probability of response is assumed to change monotonically as each of the categorical variables changes level. A probability model is used in which the response is binomial with parameters pij for each cell (i, j) and the number of observations in each cell is multinomial. Estimation approaches that incorporate Gibbs sampling with order restrictions on pij induced via a prior distribution, two-dimensional isotonic regression and multiple imputation to handle missing values are considered. The methods are compared in a simulation study. Using a fully Bayesian approach with a strong prior distribution to induce ordering can lead to large gains in efficiency, but can also induce bias. Utilizing isotonic regression can lead to modest gains in efficiency, while minimizing bias and guaranteeing that the order constraints are satisfied. A hybrid of isotonic regression and Gibbs sampling appears to work well across a variety of scenarios. The methods are applied to a pancreatic cancer case-control study with two biomarkers. Copyright © 2007 John Wiley & Sons, Ltd.

Authors
Taylor, JMG; Wang, L; Li, Z
MLA Citation
Taylor, JMG, Wang, L, and Li, Z. "Analysis on binary responses with ordered covariates and missing data." Statistics in Medicine 26.18 (2007): 3443-3458.
PMID
17219376
Source
scival
Published In
Statistics in Medicine
Volume
26
Issue
18
Publish Date
2007
Start Page
3443
End Page
3458
DOI
10.1002/sim.2815

Comparing an experimental agent to a standard agent: Relative merits of a one-arm or randomized two-arm Phase II design

Background: Phase II clinical trials in cancer are used to assess whether a new agent has sufficiently promising efficacy to proceed on to a larger definitive study comparing the new agent to a standard agent. Purpose: A crucial issue in determining the usefulness of a one-arm design is the uncertainty of the historical response rate of the standard therapy. Therefore, we contrast the usual one-arm design of a Phase II trial with a randomized two-arm design that uses the same number of patients. Methods: We use simulations and analytical approximations to compare the two designs under a range of realistic values for the historical rate uncertainty and a range of treatment effects. We also extend the simulation model to compare the efficiency of the two designs in settings where multiple Phase II studies are used to make decisions about moving on to a Phase III study. Results: For a one-arm design the probability of correctly identifying an effective experimental agent tends to be at least 0.7 in the cases considered, with the corresponding value for a randomized two-arm design within 0.05-0.10 above or below the one-arm design. An increase in total sample size from 30 patients to 80 patients tends to increase the probability of correctly identifying an effective experiment agent more in the two-arm design than the the one-arm design, particularly when the uncertainty in the historical response rate is large. Limitations: These results for binary response measures are derived from the specific scenarios and assumptions considered in the simulation study and may not apply to situations outside the range considered. Conclusions: We find that a one-arm design is preferred for small sample sizes, but a two-arm design may be preferred with larger sample sizes or if the uncertainty in the historical response rates is large. © Society for Clinical Trials 2006.

Authors
Taylor, JMG; Braun, TM; Li, Z
MLA Citation
Taylor, JMG, Braun, TM, and Li, Z. "Comparing an experimental agent to a standard agent: Relative merits of a one-arm or randomized two-arm Phase II design." Clinical Trials 3.4 (2006): 335-348.
PMID
17060208
Source
scival
Published In
Clinical Trials
Volume
3
Issue
4
Publish Date
2006
Start Page
335
End Page
348
DOI
10.1177/1740774506070654
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